Indeterminate cell histiocytosis: A systematic review of the literature with a comprehensive revision of clinical, histopathological, and molecular features.

Indeterminate cell histiocytosis (ICH) is a very rare histiocytic disorder, primarily involving the skin. It affects more frequently adults, often presenting with a generalized papular eruption, and needs to be differentiated from other neoplastic, paraneoplastic, and infectious diseases through clinical and histological examination. The knowledge on ICH is limited to case reports and small series. Thus, the lack of larger multicentric studies has prevented recognizing and addressing the specific clinical need of the entity. In this systematic review, we comprehensively analysed the medical literature describing histologically-confirmed cases of ICH and divided the patients into epidemiologically and clinically different groups. We demonstrate that ICH in adulthood is strongly associated with the development of haematological (and especially myeloid) neoplasms. In this subset of patients, we identify blastic morphology of neoplastic cells as a novel independent prognostic factor and an early histopathological predictor of an associated myeloid neoplasm. Moreover, we highlight that even though ICH may also present in childhood, these patients often show indolent behaviour. Genetically, ICH emerges as a heterogeneous condition. While patients with associated myeloid neoplasms are enriched in pERK pathway gene mutations, in others a specific ETV3::NCOA2 rearrangement is described. We finally reviewe the nosology of ICH since its first description, its possible cell of origin, and summarize the therapeutic options reported for each different clinical subgroup. With this work, we hope to foster studies on rare cutaneous histiocytosis and their comprehensive multidisciplinary characterization.

Total synthesis of the complex taxane diterpene canataxpropellane.

Canataxpropellane belongs to the medicinally important taxane diterpene family. The most prominent congener, Taxol, is one of the most commonly used anticancer agent in clinics today. Canataxpropellane exhibits a taxane skeleton with three additional transannular C-C bonds, resulting in a total of six contiguous quaternary carbons, of which four are located on a cyclobutane ring. Unfortunately, isolation of canataxpropellane from natural sources is inefficient. Here, we report a total synthesis of (-)-canataxpropellane in 26 steps and 0.5% overall yield from a known intermediate corresponding to 29 steps from commercial material. The core structure of the (-)-canataxpropellane (2) was assembled in two steps using a Diels-Alder/ortho-alkene-arene photocycloaddition sequence. Enantioselectivity was introduced by designing chiral siloxanes to serve as auxiliaries in the Diels-Alder reaction.

Rational Design of Antiangiogenic Helical Oligopeptides Targeting the Vascular Endothelial Growth Factor Receptors.

Tumor angiogenesis, essential for cancer development, is regulated mainly by vascular endothelial growth factors (VEGFs) and their receptors (VEGFRs), which are overexpressed in cancer cells. Therefore, the VEGF/VEGFR interaction represents a promising pharmaceutical target to fight cancer progression. The VEGF surface interacting with VEGFRs comprises a short α-helix. In this work, helical oligopeptides mimicking the VEGF-C helix were rationally designed based on structural analyses and computational studies. The helical conformation was stabilized by optimizing intramolecular interactions and by introducing helix-inducing Cα,α-disubstituted amino acids. The conformational features of the synthetic peptides were characterized by circular dichroism and nuclear magnetic resonance, and their receptor binding properties and antiangiogenic activity were determined. The best hits exhibited antiangiogenic activity in vitro at nanomolar concentrations and were resistant to proteolytic degradation.

Laparoscopic Incisional and Ventral Hernia Repair with Absorbable Tacks in a Long Term Follow-up: A Retrospective Control Study.

BACKGROUND: Laparoscopic Incisional and Ventral Hernia Repair (LIVHR) is a safe and worldwide accepted procedure performed using absorbable tacks. The aim of the study was to evaluate recurrence rate in a long term follow-up and whether the results of laparoscopic IVH repair in the elderly (≥65 years old) are different with respect to results obtained in younger patients. METHODS: One hundred and twenty-nine consecutive patients (74 women and 55 men, median age 67 years, range = 30-87 years) with ventral (N = 42, 32.5%) or post incisional (N = 87, 67.5%) hernia were enrolled in the study. Patients were divided into two groups according to their age: group A (N = 55, 42.6%) aged <65 years and group B (N = 74, 57.4%) aged ≥65 years. RESULTS: The mean operative time was not significantly different between groups (66.7 ± 37 vs. 74 ± 48.4 min, p = 0.4). To the end of 2016, seven recurrences had occurred (group A = 3, group B = 4, p = 1). Complications occurred in 8 (16%) patients in group A and 21 (28.3%) patients in group B. CONCLUSION: In conclusion, our results confirm that the use of absorbable tacks does not increase recurrence frequency and laparoscopic incisional and ventral repair is a safety procedure also in elderly patients.

Arnica compositum, Hekla lava and Acidum Nitricum Together are Superior to Arnica compositum Alone in the Local Treatment of Symptomatic Calcific Periarthritis of the Shoulder: A Pilot Study.

BACKGROUND: To evaluate the usefulness of Arnica compositum (AC) + Acidum nitricum (AN) + Hekla lava (HL) ointment in Emergency Medicine Department (EMD) as alternative nonpharmacological local treatment of patients with symptomatic calcific periarthritis of the shoulder (CPS) and to compare the effectiveness of this mixture against AC ointment alone. METHODS: A series of 41 consecutive patients (20 women, 19 men, median age 49 years, range 25-80 years) with non-traumatic painful unilateral CPS were randomly assigned to receive local treatment with AC+AN+HL ointment mixture (Group A, cases, N=21) or AC ointment alone (Group B, controls, N=20). The radiological Gartner classification of the CPS, and the quantification of pre- and post-treatment pain intensity using a Visual Analogue Scale (VAS) were obtained. The orthopedic evaluation of Shoulder Motion (SM) was also performed. The use of painkillers was reported as a number of doses needed. RESULTS: Age, gender distribution, Gartner type, main calcification size, baseline VAS (VAS-0) and degree of SM did not differ (p=NS) between Groups. After 3-day therapy, the reduction of pain in Group A (4.5±2.5) was superior to that observed in Group B (2.7±2.6) (p =0.03). The same result was observed in the improvement of SM in Group A (69.4±24.9) than in Group B (51.1±21.1) (p =0.015). No local or general adverse effects were noted. The number of doses of paracetamol was similar, but Group A patients used less ibuprofen (p =0.007). CONCLUSION: Local administration of the AC+AN+HL ointment mixture, which in our pilot study was superior to AC alone, could be safely suggested as an alternative uneventful treatment of patients with CPS.

Investigating the Interaction of Cyclic RGD Peptidomimetics with αVß6 Integrin by Biochemical and Molecular Docking Studies.

The interaction of a small library of cyclic RGD (Arg-Gly-Asp) peptidomimetics with αVß6 integrin has been investigated by means of competitive solid phase binding assays to the isolated receptor and docking calculations in the crystal structure of the αVß6 binding site. To this aim, a rigid receptor-flexible ligand docking protocol has been set up and then applied to predict the binding mode of the cyclic RGD peptidomimetics to αVß6 integrin. Although the RGD interaction with αVß6 recapitulates the RGD binding mode observed in αVß3, differences between the integrin binding pockets can strongly affect the ligand binding ability. In general, the peptidomimetics exhibited IC50 values for integrin αVß6 (i.e., the concentration of compound required for 50% inhibition of biotinylated fibronectin binding to isolated αVß6 integrin) in the nanomolar range (77-345 nM), about 10-100 times higher than those for the related αVß3 receptor, with a single notable ligand displaying a low nanomolar IC50 value (2.3 nM). Insights from the properties of the binding pocket combined with the analysis of the docking poses provided a rationale for ligand recognition and selectivity.

Tumor Targeting with an isoDGR-Drug Conjugate.

Herein we report the first example of an isoDGR-drug conjugate (2), designed to release paclitaxel selectively within cancer cells expressing integrin αV ß3 . Conjugate 2 was synthesized by connecting the isoDGR peptidomimetic 5 with paclitaxel via the lysosomally cleavable Val-Ala dipeptide linker. Conjugate 2 displayed a low nanomolar affinity for the purified integrin αV ß3 receptor (IC50 =11.0 nm). The tumor targeting ability of conjugate 2 was assessed in vitro in anti-proliferative assays on two isogenic cancer cell lines characterized by different integrin αV ß3 expression: human glioblastoma U87 (αV ß3 +) and U87 ß3 -KO (αV ß3 -). The isoDGR-PTX conjugate 2 displayed a remarkable targeting index (TI=9.9), especially when compared to the strictly related RGD-PTX conjugate 4 (TI=2.4).

Synthesis, Characterization, and Biological Evaluation of a Dual-Action Ligand Targeting αvß3 Integrin and VEGF Receptors.

A dual-action ligand targeting both integrin αVß3 and vascular endothelial growth factor receptors (VEGFRs), was synthesized via conjugation of a cyclic peptidomimetic αVß3 Arg-Gly-Asp (RGD) ligand with a decapentapeptide. The latter was obtained from a known VEGFR antagonist by acetylation at the Lys13 side chain. Functionalization of the precursor ligands was carried out in solution and in the solid phase, affording two fragments: an alkyne VEGFR ligand and the azide integrin αVß3 ligand, which were conjugated by click chemistry. Circular dichroism studies confirmed that both the RGD and VEGFR ligand portions of the dual-action compound substantially adopt the biologically active conformation. In vitro binding assays on isolated integrin αVß3 and VEGFR-1 showed that the dual-action conjugate retains a good level of affinity for both its target receptors, although with one order of magnitude (10/20 times) decrease in potency. The dual-action ligand strongly inhibited the VEGF-induced morphogenesis in Human Umbilical Vein Endothelial Cells (HUVECs). Remarkably, its efficiency in preventing the formation of new blood vessels was similar to that of the original individual ligands, despite the worse affinity towards integrin αVß3 and VEGFR-1.

Laparoscopic Totally Extraperitoneal Inguinal Hernia Repair in the Elderly: A Prospective Control Study.

Inguinal hernia (IH) repair can be obtained with both open and laparoscopic techniques, which are usually performed using a transabdominal preperitoneal (TAPP) or a totally extraperitoneal (TEP) approach. The aim of the study was to evaluate whether the results of laparoscopic TEP IH repair in the elderly (≥65 years old) are different with respect to results obtained in younger patients. One hundred and four consecutive patients (four women and 100 men, median age of 57 years, range=21-85 years) with unilateral (N=21, 20.2%) or bilateral (N=83, 79.8%) IH were prospectively enrolled in the study. Patients were divided into two groups according to their age: group A (N=68, 65.4%) aged <65 years and group B (N=36, 34.6%) aged ≥65 years. The mean operative time was not significantly different between groups (48±20 vs. 52±20 min, p=0.33). One case of increased PaCO2 was observed in each group (p=0.72) and two and one case of pneumoperitoneum (p=0.57) in groups A and B, respectively. Two (1.9%) patients (one in each group; p=0.55) required TEP conversion. Mild postoperative complications developed in four patients of each group (p=0.44). After one-year follow-up, three (2.9%) recurrences occurred (group 1=1, group 2=2, p=0.55), both in patients who had undergone direct IH repair. The overall postoperative relative risk of complications related to age was 1.08 (95% confidence interval=0.91-1.27, p=0.53). In conclusion, our results suggest that in patients with IH scheduled for TEP repair, age does not represent a contraindication to surgery in terms of complication rate and postoperative results.

Cyclic isoDGR and RGD peptidomimetics containing bifunctional diketopiperazine scaffolds are integrin antagonists.

The cyclo[DKP-isoDGR] peptidomimetics 2-5, containing bifunctional diketopiperazine (DKP) scaffolds that differ in the configuration of the two DKP stereocenters and in the substitution at the DKP nitrogen atoms, were prepared and examined in vitro in competitive binding assays with purified αv ß3 and αv ß5 integrin receptors. IC50 values ranged from low nanomolar (ligand 3) to submicromolar with αv ß3 integrin. The biological activities of ligands cyclo[DKP3-RGD] 1 and cyclo[DKP3-isoDGR] 3, bearing the same bifunctional DKP scaffold and showing similar αV ß3 integrin binding values, were compared in terms of their cellular effects in human U373 glioblastoma cells. Compounds 1 and 3 displayed overlapping inhibitory effects on the FAK/Akt integrin activated transduction pathway and on integrin-mediated cell infiltration processes, and qualify therefore, despite the different RGD and isoDGR sequences, as integrin antagonists. Both compounds induced apoptosis in glioma cells after 72 hour treatment.

The effects of acupuncture after thyroid surgery: A randomized, controlled trial.

BACKGROUND: Acupuncture is a safe and well-tolerated treatment for pain relief. Previous studies supported the effectiveness of several acupuncture techniques for postoperative pain. The aim of this randomized, controlled trial was to evaluate the efficacy of acupuncture in reducing pain after thyroid surgery. METHODS: We randomized 121 patients to a control group (undergoing only standard postoperative analgesic treatment with acetaminophen) and an acupuncture group, undergoing also either electroacupuncture (EA) or traditional acupuncture (TA). Pain was measured according to intraoperative remifentanil use, acetaminophen daily intake, Numeric Rating Scale (NRS), and McGill Pain Questionnaire on postoperative days (POD) 1-3. RESULTS: Acupuncture group required less acetaminophen than controls at POD 2 (P = .01) and 3 (P = .016). EA patients required less remifentanil (P = .032) and acetaminophen than controls at POD 2 (P = .004) and 3 (P = .008). EA patients showed a trend toward better NRS and McGill scores from POD 1 to 3 compared with controls. EA patients had a lower remifentanil requirement and better NRS and McGill scores than TA patients. No differences occurred between TA patients and controls. CONCLUSION: Acupuncture may be effective in reducing pain after thyroid surgery. EA is more useful; TA achieves no significant effects.

Long-term outcome of stapled transanal rectal resection (STARR) versus stapled hemorrhoidopexys (STH) for grade III-IV hemorrhoids: preliminary results.

Circular stapled transanal hemorrhoidopexy (STH) was first introduced by A. Longo for the correction of internal mucosal prolapse and obstructed defecation and in 1998, was proposed as alternative to conventional excisional hemorrhoidectomy. More recently, stapled transanal rectal resection (STARR) has gradually gained popularity, as the Longo procedure, in the treatment of hemorrhoids. The aim of our study was to evaluate the usefulness of STARR as alternative to STH in patients with grade III (n=218, 68.1%) and IV (n=102, 31.9%) hemorrhoids. A group of 320 consecutive patients (median age=51 years; range=16-85) underwent STH (n=281) or STARR (n=39) procedure. The rate of postoperative bleeding (53.8% vs. 74.4%, p<0.01) was significantly reduced in patients who underwent STARR procedure, which required a longer (45 ± 22 vs. 26 ± 11 min, p<0.01) operative time. There were no differences between groups with regard to use of painkillers, postoperative pain intensity, short- (three months) and long-term (one and three years) residual pain, soiling, incontinence and urgency. Patients treated with the STARR procedure had lower recurrence rate of hemorrhoids and a lower incidence of prolapse, both at one year (none vs. 1.4%, p=0.593 and 2.6% vs. 5.3%, p=0.396, respectively) and at two years (none vs. 6.8%, p=0.078 and none vs. 13.2%, p=0.012, respectively). The one-year (9.0 ± 1.8 vs. 9.4 ± 0.7, p=0.171) and two-year (9.6 ± 0.8 vs. 9.1 ± 1.7, p=0.072) general satisfaction was similar but higher in STARR patients than in the STH group. In conclusion, according to our preliminary results, the STARR procedure leads to a lower incidence of complications and recurrences and should be considered for patients with grade III or IV hemorrhoids previously selected for stapled hemorrhoidectomy, as a promising alternative to STH.

Touch imprint cytology and frozen-section analysis for intraoperative evaluation of sentinel nodes in early breast cancer.

Sentinel lymph node biopsy (SLNB) is currently the suggested axillary staging procedure in patients with early-stage breast cancer (BC) and usually requires intraoperative frozen-section (FS) examination of the removed nodes. However, other techniques, such as touch imprint cytology (IC), real-time reverse transcriptase-polymerase chain reaction and rapid cytokeratin immunostaining on FS may be used. The aim of this preliminary study was to assess the usefulness of intraoperative IC and FS section analysis together in improving the accuracy of sentinel lymph node evaluation in patients with early BC, who underwent SLNB. A series of 126 consecutive women (median age 52, range 34-71 years) with T1 (≤20 mm) BC, were prospectively enrolled in the study. A total of 221 axillary nodes were processed for both IC and FS intraoperative evaluation. Final pathology revealed 74 out of 221 (33.5%) nodes with metastasis, out of which 51 (68.9%) had macrometastases. Overall, 31 out of 126 (24.6%) patients were staged as having pN1mi or pN1a. The sensitivity, specificity, and accuracy in detecting metastases were 75.7%, 100% and 91.9% for FS, 70.3%, 98.6% and 89.1% for IC, and 89.2%, 100% and 96.0% for IC+FS together, respectively. The sensitivity of FS and IC did not differ significantly (p=0.46), while the combination of FS+IC showed a higher sensitivity (p=0.03), and similar accuracy. Our preliminary data confirm that IC is a simple and rapid technique with good sensitivity, suggesting that the combination of FS and IC may be useful in all patients requiring intraoperative SLNB evaluation.

Arterial blood pressure, serum calcium and PTH in elderly men with parathyroid tumors and primary hyperparathyroidism.

In patients with parathyroid tumors and primary hyperparathyroidism (PHPT), the relationship between arterial blood pressure (BP) and both serum calcium and parathyroid hormone (PTH) is still unclear. The aim of this study was to investigate whether a correlation exists between BP and the main biochemical parameters in men with confirmed sporadic PHPT due to a solitary parathyroid adenoma. A series of 38 elderly (>64 years) men (median age 69 years, range 65-78 years) were enrolled in the study. Twenty-nine (76.3%) were asymptomatic, while 9 (23.7%) had renal diseases (i.e. renal stones, impaired renal function). The main preoperative biochemical parameters were the following: serum calcium=2.77±0.25 mmol/l, PTH=166.5±157.0 ng/l, alkaline phosphatase (ALP)=107.6±37.0 U/l, and creatinine=82.5±8.1 µmol/l. In each patient, the BP was recorded three times at 2-3 min intervals using an automatic device, and the mean values were recorded. All patients successfully underwent parathyroidectomy. As expected, there was a significant relationship between age and both systolic and diastolic BP (ß=0.39, p=0.018; ß=0.41, p=0.014, respectively). There was also a correlation between systolic and diastolic BP (ß=0.39, p=0.01) and between serum calcium and PTH (ß=0.51, p=0.008). A weak relationship (ß=0.28, p=0.04) between serum calcium and creatinine was also found. However, no significant relationship between systolic or diastolic BP and serum calcium (ß=0.012, p=0.94; ß=0.065, p=0.71) or PTH (ß=0.08, p=0.65; ß=0.17, p=0.32), respectively, was observed. In conclusion, our study confirms that in men with parathyroid tumors and PHPT, the BP values are independent of both serum calcium and PTH levels.

Endothelial activation markers soluble E-selectin and von Willebrand factor in primary hyperparathyroidism.

The aim of the study was to investigate the possible alteration of endothelial activity and its reversibility, by the measurement of von Willebrand factor (vWF) and soluble E-selectin (sES) in patients with primary hyperparathyroidism (PHPT), before and after successful parathyroidectomy. Twenty-two patients with confirmed PHPT were prospectively enrolled in the study. Sixteen sex- and age-matched healthy volunteers were used as the control group. The baseline levels of both vWF (146.1 ± 29.1 vs. 118.2 ± 26.3 U/dL, p=0.004) and sES (47.1 ± 19.7 vs. 34.2 ± 13.2 ng/mL, p=0.029) were higher in the patients with PHPT, while at the 6-month follow-up, vWF decreased significantly (120.4 ± 27.3 U/dL, p=0.004) and sES was normal (41.2 ± 21.1 ng/mL, p=NS). No correlation (p=NS) was found between any of the baseline biochemical parameters. In conclusion, some markers of endothelial activation may be higher in patients with PHPT with respect to controls and the decrease of vWF after parathyroidectomy should be considered as a biochemical parameter of improved endothelial function.

Axillary node sampling in conjunction with sentinel node biopsy in patients with breast cancer. A prospective preliminary study.

In patients with breast cancer (BC), axillary lymph node sampling (ALNS) is a reliable procedure with low morbidity, alternative or complementary to sentinel lymph node biopsy (SLNB), which may improve the detection rate of axillary node metastases as compared to SLNB alone in staging the axilla. The aim of this study was to assess the usefulness of ALNS in conjunction with SLNB in improving the sensitivity of SLNB alone at frozen section examination. One hundred and twelve women (median age 56 years, range 29-71 years) with BC underwent SLNB using a combined radioisotope and isosulfan blue dye technique. Two groups of age- and tumor size-matched patients were prospectively randomized: Group A (SLNB alone, 55 women) and group B (SLNB plus ALNS, 57 women). Intraoperative examination showed SN involvement in 32 (28.6%) patients: group A = 14 (25.5%), group B = 18 (31.6%), whilst the final pathology showed axillary node involvement in 7 further cases (group A = 5, group B = 2). The sensitivity and accuracy were 73.7% vs. 90.0% (p = 0.23) and 90.9% vs. 94.7% (p = 0.49), group A vs. B, respectively. Multivariate analysis showed that age >65 years and body mass index independently correlated with the amount of axillary drainage in both groups, which was 47.5 ± 11.3 and 49.6 ± 12.2 ml (A vs. B, p = NS), respectively. In conclusion, in our preliminary study, ALNS in conjunction with SLNB is a low-risk procedure, useful to reduce the false-negative rate of SLNB and to improve the accuracy of intraoperative evaluation of the axillary nodes in patients with BC.

The usefulness of preoperative ultrasonographic identification of nonrecurrent inferior laryngeal nerve in neck surgery.

BACKGROUNDS AND AIMS: Nonrecurrent inferior laryngeal nerve (ILN) represents a risk factor for injury during neck surgery. It is associated to arterial abnormalities (absence of the brachiocephalic trunk and arteria lusoria) that can be identified by ultrasonography. The aim of the study was to verify the usefulness of preoperative ultrasonography in the research of nonrecurrent ILN by the means of identification of arterial abnormalities and the impact on ILN morbidity. PATIENTS AND METHODS: The study included 750 patients who underwent neck surgery with right-side ILN dissection. A preoperative ultrasonography aimed to identify arterial abnormalities associated to nonrecurrent ILN was performed in 400 patients (Group A) while no preoperative attempts were performed in the remaining patients (Group B). Patients' characteristics, time for intraoperative identification of the ILN, and morbidity were compared. RESULTS: Five and four nonrecurrent ILN were identified in groups A and B, respectively (p = NS). Preoperative ultrasonography correctly predicted nonrecurrent ILN in all cases (accuracy 100%). Nonrecurrent ILN palsy never occurred in group A, while three cases occurred in group B (p < 0.05). The mean time for intraoperative identification of both nonrecurrent and normally recurrent ILN was significantly shorter in group A (p < 0.01). CONCLUSIONS: Preoperative ultrasonography can correctly identify nonrecurrent ILN, allowing earlier nerve identification and prevention of injuries.

PCNA-LII, Ki-67 immunostaining, p53 activity and histopathological variables in predicting the clinical outcome in patients with parathyroid carcinoma.

Parathyroid carcinoma is uncommon and no reliable histological markers are available for predicting the clinical outcome of patients. The aim of this study was to assess the correlation between survival, histopatological markers, proliferating cell nuclear antigen (PCNA), Ki-67 antigen and the expression of the p53 nuclear protein in patients with confirmed parathyroid carcinoma (PC). The routine histological specimens from 15 patients (11 men, 4-women, median age 65 years) with confirmed PC who had died of the disease were reviewed. New specimens were also stained with the streptavidin-biotin-peroxidase complex standard technique. The labelling index (LI) of PCNA was quantified by counting 1000 cells from multiple areas in a random fashion, while immunostaining of both Ki-67 and p53 was evaluated as the percentage of positive cells. The PCNA-LI, Ki-67 (%) and p53 (%) values were 14.9 +/- 4.1 (median 13, range 2-70), 13.9 +/- 3.9 (median 11%, range 3-65%) and 38.5 +/- 4.6 (median 29%, range 19-65%), respectively. There was an inverse correlation between age of the patients and p53 (R = -0.73, p = 0.002), but no correlation with both PCNA-LI (R = 0.07, p = 0.72) and Ki-67 (R = -0.07, p = 0.79). A significant relationship (R = 0.93, p < 0.01) between PCNA-LI and Ki-67 was found, while p53 did not correlate with either PCNA-LI (R = -0.11, p = 0.71) or Ki-67 (R = -0.05, p = 0.86). An inverse correlation (R = -0.63, p = 0.01) between survival and the presence of spindle cells and coagulation necrosis together in the standard slides was observed, but there was no correlation (p = NS) between survival and PCNA-LI (R = 0.05), Ki -67 (R = 0.05) or p53 (R = 0.25). In conclusion, none of the tested immunohistochemical markers were useful in predicting the clinical outcome of patients with PC. However, the presence of spindle cells and coagulation necrosis together in the standard specimens should be considered as a negative prognostic factor.